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Issues and progress with protein kinase inhibitors for cancer treatment

Key Points

  • The success of the tyrosine-kinase inhibitor STI571 (Gleevec/Glivec) in the treatment of chronic myelogenous leukaemia has spurred considerable efforts to develop other kinase inhibitors for the treatment of a wide range of cancers.

  • However, the molecularly targeted nature of these drugs poses several novel challenges in their clinical development as compared with the development of traditional cytotoxic drugs.

  • Issues considered in this review include:

  • Which kinase to target with what type of drug?

  • Which disease to target, and when?

  • How to build combinations with standard agents

  • Strategies to address the development challenges raised by these issues are put forward.

Abstract

Identification of the key roles of protein kinases in cancer has led to extensive efforts to develop kinase inhibitors for the treatment of a wide range of cancers, and more than 30 such agents are now in clinical trials. Here, we consider the crucial issues in the development of kinase inhibitors for cancer, and discuss strategies to address the challenges raised by these issues in the light of preclinical and clinical experiences so far.

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Figure 1: Kinase targets and agents.
Figure 2: Several mechanisms can inhibit kinase signalling.

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DATABASES

Cancer.gov

Chronic myelogenous leukaemia

Swiss-Prot

Akt

AP-1

CDK1

cyclin D1

EGF

EGFR

Fos

Jun

MEK1

MEK2

PDK1

PTEN

Raf-1

VEGF

Glossary

METASTASIS

The dissemination of cancer cells via the bloodstream or lymphatic system to other parts of the body, where they produce further tissue damage.

LYMPHOID

A term that describes the type of tissue found in the lymph nodes, tonsils, spleen, and thymus. It is responsible for producing lymphocytes and therefore contributes to the body's defence against infection.

MYELOID

A term that describes tissue within red bone marrow that produces the blood cells.

KARYOTYPE

A complete description of the chromosomes present in a cell. It is characterized by numerical and structural abnormalities in most cancers.

FAMILIAL ADENOMATOUS POLYPOSIS

A genetic disorder characterized by the development of multiple intestinal polyps that are precursor lesions for colon carcinoma.

THROMBOTIC

A term that describes the obstruction of a blood vessel by a mass of blood cells and fibrin (thrombus), which can result from excessive blood clotting.

POSITRON EMISSION TOMOGRAPHY

An imaging technique that is used to detect decaying nuclides, such as 15O, 13N, 11C, 18F, 124I and 94mTc.

TUMOUR XENOGRAFT

Generally refers to the growth of human tumour cells as tumours in immuno-compromised mice.

IC50

The half-maximal inhibitory concentration.

TRANSFORMING

A term that describes the processes through which normal cells acquire malignant character.

PARTIAL THROMBOPLASTIN TIME

A test to assess the function of specific proteins required to form blood clots.

ANASARCA

Generalized oedema.

ERYTHEMA

Abnormal redness of skin.

SKIN DESQUAMATION

Sloughing of skin layer.

PEARSON CORRELATION COEFFICIENT

Pearson's correlation coefficient (r) expresses the degree of linear relationship. Pearson's r values can range between −1.00 to +1.00. A correlation coefficient of +1.00 signifies a perfect positive relationship, whereas −1.00 denotes a perfect negative relationship. The smallest correlation is zero.

THROMBOCYTOPENIA

A reduction in the number of platelets.

NEUTROPENIA

A reduction in the number of neutrophils.

MUCOSITIS

Inflammation of the mucosa.

ASTHENIA

Generalized weakness and debility.

DYSPNOEA

Shortness of breath and discomfort of breathing.

URTICARIA

Red itchy skin lesions.

PRURITIS

Itchiness.

FOLLICULITIS

Inflammation around hair follicles.

LEUKOPENIA

Low white blood cell (leukocyte) count.

STOMATITIS

Inflammation of the lining of the mouth.

MYELOSUPPRESSION

Depressed production of blood cells deriving from the myeloid lineage, including platelets, some leukocytes and erythrocytes. Because many anticancer drugs suppress the growth or proliferation of rapidly dividing cells, myelosuppression is a common side effect.

PNEUMONITIS

Inflammation of the lung tissues.

PARACRINE

Describing an agent secreted from a cell that acts on other cells in the local environment.

AUTOCRINE

Describing an agent secreted from a cell that acts on the cell in which it is produced.

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Dancey, J., Sausville, E. Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2, 296–313 (2003). https://doi.org/10.1038/nrd1066

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